A major endeavor in neuroscience is to elucidate the mechanisms by which the brain stores information acquired through learning. To make progress towards a complete understanding of memory formation, model systems that allow the experimenter to relate changes in specific synapses to specific behavior are essential. We propose to study a pheromone memory model that is ideally suited for integrating several levels of analysis: from molecules to behavior. Female mice form memory to the male's pheromones during mating through single-trial learning and retain the information for a significant period of their lifetime. The memory formation occurs only if two neurotransmitter inputs, glutamate and norepinephrine (NE), coincide in the accessory olfactory bulb (AOB), the locus of pheromone memory. Glutamate and NE somehow lead to structural and functional modifications of the AOB synapses. Our overall goal is to understand how coincidence of glutamate and NE is detected, and to elucidate the signaling mechanisms downstream of glutamate and NE that control formation of long-term pheromone memory. Our preliminary results suggest that protein kinase C (PKC) has a critical signaling role. Our first aim is to use a novel approach that uses specific activators and inhibitors of PKC isoforms in electrophysiological experiments in combination with biochemical experiments to identify the isoform of PKC that detects coincident glutamate and NE inputs in the AOB. Our second aim is to develop a method to knock down the expression of a specific PKC isoform via virally-mediated delivery of small interfering RNAs. The proposed experiments would launch a research program that has enormous potential to address unanswered questions pertaining to mammalian long-term memory. In the pheromone memory model the neural circuitry is well delineated, the behavioral output is unambiguous, and genetic manipulations can be readily done. Therefore, this model system has unparalleled advantages over other systems in linking molecular changes in a specific synapse to changes in a specific behavior. Clarification of the mechanisms governing synaptic plasticity would be beneficial for discovering the causes of memory deficits and cognitive dysfunctions that occur in abnormalities like posttraumatic stress disorder, schizophrenia and Alzheimer's disease, and for devising therapeutic strategies.